This center began with a strong basic science and engineering focus on better understanding nucleoprotein machines, specifically looking at assembly and function of the non-homologous end joining (NHEJ) molecular complex. The purpose was to use the pathway for genetic therapies. It became apparent that NHEJ could not be understood isolated from homologous recombination (HR), which competes with NHEJ and affords better possibilities for gene correction. The investigators developed protein tagging strategies and imaging methods to study the NHEJ and HR complexes at work in the living cell.

The Nanomedicine program was designed to modulate an intracellular nanoscale complex to treat a specific disease target. The researchers at this center determined that using DNA repair pathways for gene editing is feasible by combining their knowledge about the repair pathways with the newest tools for editing the genome. Activation of gene correction by HR began using Zinc-finger nucleases (ZFNs). Most recently, newly engineered transcription activator-like effector nucleases (TALENs) appear to be more effective and more specific in their ability to snip a specific sequence of DNA. These nucleases, designed to break the DNA and remove the defective gene are introduced into diseased cells along with a corrected donor strand that in theory should replace the defective gene with a normal copy.

TRANSLATIONAL GOALS

The primary translational target of the center is gene correction of the defective beta-globin gene in a mouse model of SCD. The approach is to replace defective cells by isolating hematopoietic stem/progenitor cells (HSPCs) that carry the sickle mutation, correcting this mutation ex vivo, and transplanting the gene-corrected HSPCs back into the SCD patient, thereby supplying healthy red blood cells to ameliorate or even cure the disease. The near-term goal of the center is to lay the foundation for a clinical trial to determine the efficacy of the gene correction approach in treating SCD patients. This strategy includes the following major tasks: